WO1996038145A1 - Procedes destines a inhiber la migration de cellules de muscles lisses vasculaires - Google Patents

Procedes destines a inhiber la migration de cellules de muscles lisses vasculaires Download PDF

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Publication number
WO1996038145A1
WO1996038145A1 PCT/US1996/008037 US9608037W WO9638145A1 WO 1996038145 A1 WO1996038145 A1 WO 1996038145A1 US 9608037 W US9608037 W US 9608037W WO 9638145 A1 WO9638145 A1 WO 9638145A1
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WIPO (PCT)
Prior art keywords
smooth muscle
cell migration
compound
muscle cell
vascular smooth
Prior art date
Application number
PCT/US1996/008037
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English (en)
Inventor
Jai P. Singh
Todd R. Wiernicki
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Eli Lilly And Company
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Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to RO97-02169A priority Critical patent/RO117996B1/ro
Priority to UA97115726A priority patent/UA42835C2/uk
Priority to EA199700450A priority patent/EA000190B1/ru
Priority to NZ309390A priority patent/NZ309390A/en
Priority to JP8536654A priority patent/JPH11509836A/ja
Priority to AU59541/96A priority patent/AU707756B2/en
Priority to PL96323786A priority patent/PL323786A1/xx
Publication of WO1996038145A1 publication Critical patent/WO1996038145A1/fr
Priority to NO975369A priority patent/NO975369L/no
Priority to MXPA/A/1997/009189A priority patent/MXPA97009189A/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • vascular smooth muscle cells migrate from media to intima plays a critical role in neointima formation leading to the pathogenesis of vascular disease such as atherosclerosis, restenosis following PTCA, and vein bypass atherosclerosis (Jackson et al . , Arteriosclerosis and
  • Use of antibodies to growth factors stimulating smooth muscle cell migration or peptides that block integrin mediated cell migration have been found to inhibit neointima formation in animal models of vascular injury (Ferns et al . . Science 253 : 1129-1132, 1991., Choi et al . , J. Vase. Surg. 19 : 125-135, 1994) .
  • vascular restenosis after percutaneous transluminal coronary angioplasty has been shown to be a tissue response characterized by an early and late phase. Thrombosis and/or vasospasms may contribute to the early phase occuring hours to days after PTCA. The late phase appears to be dominated by SMC migration, proliferation and vascular remodeling. In this disease, the increased SMC accumulation by migration from media to intima contributes significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherectomy, laser angioplasty and arterial bypass graft surgery.
  • vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA) , atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure.
  • PTCA percutaneous transluminal coronary angioplasty
  • the current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See "Prevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a 'Magic Bullet'," Hermans et al . , American Heart Journal 122: 171- 187 (July 1991) .
  • Agents that inhibit the migration of smooth muscle cells are useful in the treatment and prevention of restenosis.
  • the present invention provides for the use of compounds as smooth muscle cell migration inhibitors.
  • Ri and R3 are independently hydrogen , -CH3 ,
  • R2 is pyrrolidino, hexamethyleneimino, or piperidino; and pharmaceutically acceptable salts and solvates thereof.
  • the current invention concerns the discovery that a select group of compounds, those of formula I are useful for inhibiting vascular smooth muscle cell migration.
  • the methods of treatment provided by this invention are practiced by administering to a human or other mammal in need a dose of a compound of formula I or II, or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit vascular smooth muscle cell migration.
  • inhibitor is defined to include its generally accepted meaning which includes phrophylactically treating a human subject to incurring smooth muscle cell migration, and holding in check and/or treating existing smooth muscle cell migration. As such, the present method includes both medical therapeutic and/or prophylactic treatment, as appropriate.
  • the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes.
  • the compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
  • the compounds of formula I used in the methods of the current invention can be made according to established procedures, such as those detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein.
  • the process starts with a benzo[b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group.
  • the starting compound is protected, alkylated, and deprotected to form the formula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above.
  • Substituted phenyl includes phenyl substituted once or twice with Ci-C ⁇ alkyl, C3 . -C4 alkoxy, hydroxy, nitro, chloro, fluoro, or tr(chloro or fluoro)methyl.
  • the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1, 4-dioate, hexyne-1, 4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate,
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether or benzene.
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, as well as aliphatic and aromatic amines, aliphatic diamines and hydroxy alkylamines.
  • Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylene diamine, cyclohexylamine and ethanolamine.
  • the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • compositions can be prepared by procedures known in the art.
  • the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as agaragar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium
  • the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • the coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
  • the particular dosage of a compound of formula I required to inhibit smooth muscle cell migration according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician. Generally, accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day. Such dosages will be administered to a subject in need of treatment from once to about three times each day, or more often as needed to effectively inhibit smooth muscle cell migration.
  • the local delivery of inhibitory amounts of active compound for the treatment of vascular smooth muscle cell migration or restinosis can be by a variety of techniques which administer the compound at or near the affected site.
  • Examples of local delivery techniques are not intended to be limiting but to be illustrative of the techniques available. Examples include local delivery catheters, site specific carriers, implants, direct injection, or direct applications. Local delivery by a catheter allows the administration of a pharmaceutical agent directly to the affected lesion. Examples of local delivery using a balloon catheter are described in EPO 383 492 A2 and U.S. Patent 4,636,195 (Wolinsky, January 13, 1987).
  • Local delivery by an implant describes the surgical placement of a matrix that contains the pharmaceutical agent into the lesion.
  • the implanted matrix releases the pharmaceutical agent by diffusion, chemical reaction, or solvent activators.
  • An example of local delivery by an implant is the use of a stent. Stents are designed to mechanically prevent the collapse and reocclusion of the coronary arteries. Incorporating a pharmaceutical agent into the stent delivers the drug directly to the affected site. Local delivery by this technique is described in Kohn, Pharmaceutical Technology (October, 1990) .
  • Another example is a delivery system in which a polymer that contains the pharmaceutical agent is injected into the lesion in liquid form. The polymer then cures to form the implant in situ .
  • This technique is described in PCT WO 90/03768 (Donn, April 19, 1990).
  • Another example is the delivery of a pharmaceutical agent by polymeric endoluminal sealing. This technique uses a catheter to apply a polymeric implant to the interior surface of the lumen. The pharmaceutical agent incorporated into the biodegradable polymer implant is thereby released at the surgical site. It is descibed in PCT WO 90/01969 (Schindler, August 23, 1989) .
  • microparticulates may be composed of substances such as proteins, lipids, carbohydrates or synthetic polymers. These microparticulates have the pharmaceutical agent incorporated throughout the microparticle or over the microparticle as a coating. Delivery systems incorporating microparticulates are described in Lange, Science 249 : 1527-1533 (September, 1990) and Mathiowitz, et al . , J " . App. Poly. Sci . , 26: 809 (1981) .
  • Local delivery by site specific carriers describes attaching the pharmaceutical agent to a carrier which will direct the drug to the lesion.
  • Examples of this delivery technique includes the use of carriers such as a protein ligand or a monoclonal antibody. Lange, Science 249 : 1527- 1533 (September) .
  • Local delivery by direct application includes the use of topical applications.
  • An example of a local delivery by direct application is applying the pharmaceutical agent directly to the arterial bypass graft during the surgical procedure.
  • a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceuticals bearing a basic group, such as the piperidino ring. It is also advantageous to administer such a compound by the oral route to an aging human (e.g. a post-menopausal female) . For such purposes the following oral dosage forms are available.
  • Active ingredient means a compound of formula I.
  • Hard gelatin capsules are prepared using the following:
  • the ingredients are blended, passed through a No . 45 mesh U. S . sieve , and filled into hard gelatin capsules .
  • capsule formulations of the compound of formula 1 wherein the compound is raloxifene include those shown below:
  • Silicone fluid 350 centistokes 1.7 Formulation 4 Raloxifene capsule
  • a tablet formulation is prepared using the ingredients below:
  • Active ingredient 0 . 1 - 1000 Cellulose, microcrystalline 0 - 650 Silicon dioxide, fumed 0 - 650 Stearate acid 0 - 15
  • the components are blended and compressed to form tablets .
  • tablets each containing 0.1 - 1000 mg of active ingredient are made up as follows : Formulation 7: Tablets
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Suspensions each containing 0.1 - 1000 mg of medicament per 5 mL dose are made as follows:
  • Purified water to 5 mL
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • Porcine aorta were obtained from freshly slaughtered male castrated hogs at a local slaughterhouse. Smooth muscle cells were prepared using a procedure similar to that described previously(Bonin et al . , 1989) Briefly, the aorta was cut longitudinally, and the endothelium was removed by gently scraping the lumen surface with a razor blade. The aorta was then washed several times in sterile growth medium consisting of Dubecco' s Modified Eagles Medium (DMEM) , 10% Fetal Bovine Serum, L-glutamine (2 mM) , penicillin (100 U/ml), and streptomycin (100 ug/ml) .
  • DMEM Dubecco' s Modified Eagles Medium
  • penicillin 100 U/ml
  • streptomycin 100 ug/ml
  • the strips of medial smooth muscle cells were then peeled away from the adventitia and cut into 1-2 mm pieces.
  • the explants were placed in 24 well culture dishes containing the above growth medium. Cells were observed growing from the explants within 5-7 days. After 10-14 days, the explants were removed, the cells were trypsinized, and subcultured in T75 flasks containing 15 ml of the growth medium.
  • cells were trypsinized using phenol red free trypsin/EDTA (Gibco, BRL) .
  • the cells (2.5x10 " ⁇ cells/ml) were suspended in phenol-red free DMEM/F12 containg 1% platelet poor plasma, and various concentrations of compounds of formula I.
  • One hundred uL of the cell suspension were added to the upper wells of the modified Boyden chamber.
  • the wells of the lower chamber were filled with 43 ul of DMEM/F-12 containg 1% plate poor plasma, 5ng/ml PDGF and various concentration of compounds.
  • the chambers were incubated at 37° C in 5% C ⁇ 2 for 5 hours.
  • the migration membrane was removed from the chamber and the cells from the upper side of the membrane were removed with a cotton swab.
  • the cells migrated to the lower side of the membrane were fixed in methanol and stained with Diff-Quick staining solution (Baxter) .
  • Cell migration was quantified either spectrophotometically using a microtiter plate reader (ThermoMax, Molecular Dynamics, Inc.) or by counting the cells in a 40X high power field (HPF) using an inverted microscope (Nikon, Inc.).
  • PDGF Platelet-Derived Growth Factor
  • Compound A is of the Formula I, where Ri and R 3 are hydrogen and R 2 is pyrrolidino.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne des procédés destinés à inhiber la migration de cellules de muscles lisses vasculaires, consistant à administrer à un être humain ou à d'autres mammifères nécessitant un traitement, une quantité efficace d'un composé de formule (I) ou de ses sels et solvates pharmaceutiquement acceptables. Dans la formule (I), R1 et R3 représentent indépendamment l'un de l'autre hydrogène, -CH¿3?, (a), ou (b), Ar représentant phényle éventuellement substitué; R?2¿ représente pyrrolidino, hexaméthylène-imino ou pipéridino.
PCT/US1996/008037 1995-06-01 1996-05-30 Procedes destines a inhiber la migration de cellules de muscles lisses vasculaires WO1996038145A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
RO97-02169A RO117996B1 (ro) 1995-06-01 1996-05-30 Metoda de tratament pentru inhibarea migratiei celulelor musculare netede, vasculare
UA97115726A UA42835C2 (uk) 1995-06-01 1996-05-30 Спосіб інгібування міграції клітин гладеньких м'язів судин
EA199700450A EA000190B1 (ru) 1995-06-01 1996-05-30 Способы подавления миграции сосудистых гладкомышечных клеток
NZ309390A NZ309390A (en) 1995-06-01 1996-05-30 Inhibiting vascular smooth muscle cell migration
JP8536654A JPH11509836A (ja) 1995-06-01 1996-05-30 血管平滑筋細胞の移動を阻害する方法
AU59541/96A AU707756B2 (en) 1995-06-01 1996-05-30 Methods for inhibiting vascular smooth muscle cell migration
PL96323786A PL323786A1 (en) 1995-06-01 1996-05-30 Method of inhibiting migration of vessels' smooth muscle tissue
NO975369A NO975369L (no) 1995-06-01 1997-11-21 Fremgangsmåter for å inhibere glattmuskelcellemigrering
MXPA/A/1997/009189A MXPA97009189A (en) 1995-06-01 1997-11-27 Methods to inhibit the migration of cells of the smooth muscle vascu

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/457,700 US5622975A (en) 1995-06-01 1995-06-01 Methods for inhibiting vascular smooth muscle cell migration
US08/457,700 1995-06-01

Publications (1)

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WO1996038145A1 true WO1996038145A1 (fr) 1996-12-05

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US (1) US5622975A (fr)
EP (1) EP0745384A3 (fr)
JP (1) JPH11509836A (fr)
KR (1) KR19990022053A (fr)
CN (1) CN1089237C (fr)
AU (1) AU707756B2 (fr)
CA (1) CA2222292A1 (fr)
CZ (1) CZ287958B6 (fr)
EA (1) EA000190B1 (fr)
HU (1) HUP9900851A3 (fr)
IL (1) IL118483A (fr)
MY (1) MY112973A (fr)
NO (1) NO975369L (fr)
NZ (1) NZ309390A (fr)
PL (1) PL323786A1 (fr)
RO (1) RO117996B1 (fr)
UA (1) UA42835C2 (fr)
WO (1) WO1996038145A1 (fr)
YU (1) YU32196A (fr)
ZA (1) ZA964439B (fr)

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KR19990022053A (ko) 1999-03-25
EP0745384A3 (fr) 1997-02-26
YU32196A (sh) 1999-06-15
NZ309390A (en) 2000-07-28
CN1089237C (zh) 2002-08-21
AU707756B2 (en) 1999-07-22
UA42835C2 (uk) 2001-11-15
CZ374497A3 (cs) 1998-06-17
EA199700450A1 (ru) 1998-06-25
RO117996B1 (ro) 2002-12-30
PL323786A1 (en) 1998-04-27
AU5954196A (en) 1996-12-18
EA000190B1 (ru) 1998-12-24
CA2222292A1 (fr) 1996-12-05
EP0745384A2 (fr) 1996-12-04
CZ287958B6 (cs) 2001-03-14
JPH11509836A (ja) 1999-08-31
NO975369D0 (no) 1997-11-21
NO975369L (no) 1997-11-21
MY112973A (en) 2001-10-31
ZA964439B (en) 1997-12-01
US5622975A (en) 1997-04-22
MX9709189A (es) 1998-03-31
HUP9900851A3 (en) 1999-11-29
IL118483A (en) 2000-06-29
CN1191487A (zh) 1998-08-26
IL118483A0 (en) 1996-09-12
HUP9900851A2 (hu) 1999-09-28

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